Serum Homocysteine, Pyridoxine, Folate, and Vitamin B12 Levels in Migraine: Systematic Review and Meta‐Analysis

Background Migraine, especially migraine with aura (MA), has been linked to increased risk for ischemic cerebrovascular disease. The possible role of elevated serum homocysteine (Hcy, a cause of thrombophilia) in migraine has been demonstrated by several studies. Objective The present study aims to review and meta‐analyze data from studies investigating the difference of serum Hcy and Hcy lowering vitamins between migraine patients and healthy controls (HC), as well as between patients with MA and migraine without aura (MO). Methods Literature search involved MEDLINE, Embase, CENTRAL, Google Scholar, and trial registries. The Newcastle‐Ottawa Scale was used to evaluate the quality of the retrieved studies. Standardized mean differences (SMDs) and 95% confidence intervals (95%CIs) were calculated. Funnel‐plots were utilized for the evaluation of publication bias. Results Overall, 29 (28 case‐control and 1 cross‐sectional) studies were retrieved. Meta‐analysis was indicative of higher Hcy concentration in migraine patients vs HC overall [adults and children: 16 studies, I2 = 81%, SMD = 0.41, 95%CI = (0.20, 0.61)]. Hcy was consistently elevated in adults with migraine [adults: 12 studies, I2 = 76%, SMD = 0.35, 95%CI = (0.15, 0.54); children: 1 study, SMD = 0.37, 95%CI = (−0.05, 0.79)]. Subgroup analyses reproduced the results for both adults with MA [7 studies, I2 = 83%, SMD = 0.37, 95%CI = (0.03, 0.71)] and MO [5 studies, I2 = 84%, SMD = 0.46, 95%CI = (0.03, 0.89)]. Figures for serum folate were lower in the overall comparison of migraine patients with HC [adults and children: 11 studies, I2 = 87%, SMD = −0.36, 95%CI = (−0.68, −0.05); adults: 8 studies, I2 = 6%, SMD = −0.11, 95%CI = (−0.22, 0.01); children: 1 study, SMD = −0.71, 95%CI = (−1.14, −0.29); MA adults: 4 studies, I2 = 44%, SMD = −0.16, 95%CI = (−0.35, 0.04); MO adults: 4 studies, I2 = 47%, SMD = −0.17, 95%CI = (−0.44, 0.10)]. Serum vitamin B12 levels were not different between migraine patients and HC [adults and children: 11 studies, I2 = 88%, SMD = −0.24, 95%CI = (−0.57, 0.09); adults: 8 studies, I2 = 57%, SMD = −0.10, 95%CI = (−0.28, 0.08); children: 1 study, SMD = 0.29, 95%CI = (−0.13, 0.71); MA adults: 4 studies, I2 = 63%, SMD = −0.14, 95%CI = (−0.48, 0.20); MO adults: 4 studies, I2 = 59%, SMD = −0.15, 95%CI = (−0.45, 0.15)]. Serum Hcy was lower in MO than MA [adults and children: 10 studies, I2 = 39%, SMD = 0.30, 95%CI = (0.14, 0.46), adults: 6 studies, I2 = 29%, SMD = 0.21, 95%CI = (0.09, 0